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Wagle, Nikhil; Van Allen, Eliezer M; Treacy, Daniel J; Frederick, Dennie T; Cooper, Zachary A; Taylor-Weiner, Amaro; Rosenberg, Mara; Goetz, Eva M; Sullivan, Ryan J; Farlow, Deborah N; Friedrich, Dennis C; Anderka, Kristin; Perrin, Danielle; Johannessen, Cory M; McKenna, Aaron; Cibulskis, Kristian; Kryukov, Gregory; Hodis, Eran; Lawrence, Donald P; Fisher, Sheila; Getz, Gad; Gabriel, Stacey B; Carter, Scott L; Flaherty, Keith T; Wargo, Jennifer A; Garraway, Levi A
Cancer discovery, 01/2014, Letnik: 4, Številka: 1Journal Article
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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